Treatment of amyloidogenic diseases

• US 8,613,920 B2
• Filed: 07/27/2007
• Issued: 12/24/2013
• Est. Priority Date: 07/27/2007
• Status: Active Grant

• Current Assignee: Janssen Sciences Ireland UC (Johnson & Johnson)
• Original Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth LLC (Pfizer Inc.)
• Inventors: Lieberburg, Ivan, Callaway, James, Grundman, Michael
• Primary Examiner(s): BALLARD, KIMBERLY
• Application Number:
  US12/297,636
• Publication Number:
  US 20100221187A1
• Time in Patent Office: 2,342 Days
• Field of Search: None
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/44 Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL

Abstract

The invention provides preferred dosage ranges, maximum concentrations, average concentrations and monitoring regimes for use in treatment of Alzheimer'"'"'s disease using antibodies to Aβ. The invention also provides monitoring regimes that can assess changes in symptoms or signs of the patient following treatment.

Claims

1. A method of therapeutically treating Alzheimer'"'"'s disease, comprising administering by intravenous infusion to a human patient suffering from the disease a dosage of an antibody that specifically binds to an N-terminal fragment of beta-amyloid peptide (Aβ

) with a binding affinity of at least 10⁷ M<sup>−

1</sup>, and monitoring the patient for posterior reversible encephalopathy syndrome (PRES) or vascular edema, wherein the method comprises the steps of;

(a) administering a first dosage to the patient;

(b) monitoring the patient and detecting the presence of PRES or vascular edema at a first time point;

(c) optionally administering a second dosage to the patient after the monitoring in step (b) detects presence of PRES or vascular edema;

(d) monitoring the patient and detecting the absence of PRES or vascular edema at a second time point; and

(e) administering another dosage to the patient after the monitoring in step (d) indicates absence of PRES or vascular edema,

wherein the dosages in (a) and (e) are higher than the dosage in (c) if a dosage is administered in (c).

3. The method of claim 1 or 2, wherein the antibody is a humanized antibody.

4. The method of claim 3, wherein the humanized antibody is a humanized version of mouse antibody 3D6 expressed by the hybridoma deposited under ATCC under No. PTA-5130.

5. The method of claim 4, wherein the humanized antibody is bapineuzumab.

6. The method of claim 5, wherein the first dosage is 3-5 mg/kg and the second dosage is 0.5 to 3 mg/kg.

7. The method of claim 6, wherein the second dosage is half of the first dosage.

8. The method of claim 1 or 2, wherein the dosages are administered every 8 to 16 weeks.

9. The method of claim 8, wherein the dosages are administered every 10 to 14 weeks.

10. The method of claim 9, wherein the dosages are administered every 13 weeks.

11. The method of claim 1 or 2, wherein the first and third dosages are the same.

12. The method of claim 1 or 2, wherein the first dosage is 3-5 mg/kg and the second dosage is 0.5 to 3 mg/kg.

13. The method of claim 12, wherein the second dosage is half of the first dosage.

14. The method of claim 1 or 2, wherein the monitoring comprises performing an MRI scan.

15. The method of claim 14, wherein the monitoring further comprises performing a FLAIR (Fluid Attenuated Inversion Recovery) sequence imaging.

16. The method of claim 15, further comprising reducing or suspending the second dosage based on an outcome of the FLAIR sequence imaging that is indicative of PRES or vascular edema.

17. The method of claim 14, wherein the MRI scan is every 3 months, every 6 months, or every year.

18. The method of claim 15, wherein the FLAIR sequence imaging is every 3 months, every 6 months, or every year.

19. The method of claim 14, wherein the monitoring comprises identifying of at least one clinical symptom associated with PRES or vascular edema.

20. The method of claim 19, wherein the at least one clinical symptom is selected from the group consisting of headache, nausea, vomiting, confusion, seizures, visual abnormalities, altered mental functioning, ataxia, frontal symptoms, parietal symptoms, stupor, and focal neurologic signs.

21. The method of claim 20, further comprising reducing or suspending the second dosage based on an identification of at least one clinical symptom associated with PRES or vascular edema.

22. The method of claim 14, further comprising reducing or suspending the second dosage based on an outcome of the MRI scan that is indicative of PRES or vascular edema.

23. The method of claim 22, further comprising determining presence or absence of hypertension in the patient, wherein if the patient has hypertension, the method further comprises administering an antihypertensive.

24. The method of claim 23, wherein the antihypertensive is selected from the group consisting of hydroclorothiazide, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II-receptor blockers (ARB), beta blockers, and calcium channel blockers.

25. The method of claim 22, wherein the method further comprises administering a steroid to the patient to treat the PRES or vascular edema.

26. The method of claim 25, wherein the steroid is dexamethasone.

27. The method of claim 25, wherein the steroid is methyprednisolone.

28. The method of claim 1 or 2, further comprising monitoring the patient by at least one type of assessment selected from the group of consisting of Mini-Mental State Exam (MMSE), Alzheimer'"'"'s Disease Assessment Scale-cognitive (ADAS-COG), Clinician Interview-Based Impression (CIBI), Neurological Test Battery (NTB), Disability Assessment for Dementia (DAD), Clinical Dementia Rating-sum of boxes (CDR-SOB), Neuropsychiatric Inventory (NPI), Positron Emission Tomography (PET Imaging) scan, Magnetic Resonance Imaging (MRI) scan, EKG and measurement of blood pressure.

29. The method of claim 28, wherein the assessment type is an Alzheimer'"'"'s Disease Assessment Scale-cognitive (ADAS-COG).

30. The method of claim 29, wherein the ADAS-COG is administered on multiple occasions.

31. The method of claim 28, wherein the assessment type is a Neurological Test Battery (NTB).

32. The method of claim 31, wherein the NTB is administered on multiple occasions.

33. The method of claim 28, wherein the type of assessment is an MMSE.

34. The method of claim 33, wherein the MMSE is administered on multiple occasions.

35. The method of claim 34, wherein the MMSE is performed before administering the first dosage, and at week 4, week 16, 6 months, and 1 year after administering the first dosage.

36. The method of claim 34, wherein the MMSE score measured after administration is higher than a previously assessed MMSE score.

2. A method of therapeutically treating Alzheimer'"'"'s disease, comprising administering by intravenous infusion to a human patient suffering from the disease a dosage of an antibody within a range of about 0.5 mg/kg to less than 5 mg/kg, wherein the antibody specifically binds to an N-terminal fragment of beta-amyloid peptide (Aβ

) with a binding affinity of at least 10⁷ M<sup>−

1</sup>, and monitoring the patient for posterior reversible encephalopathy syndrome (PRES) or vascular edema, wherein the method comprises the steps of;

(a) administering a first dosage to the patient;

(b) monitoring the patient and detecting the presence of PRES or vascular edema at a first time point;

(c) optionally administering a second dosage to the patient after the monitoring in step (b) detects presence of PRES or vascular edema;

(d) monitoring the patient and detecting the absence of PRES or vascular edema at a second time point; and

(e) administering another dosage to the patient after the monitoring in step (d) indicates absence of PRES or vascular edema,

wherein the dosages in (a) and (e) are higher than the dosage in (c) if a dosage is administered in (c).